Surrogate Exposure Research Articles

How well does a single blood sample represent long-term exposure for epidemiological studies of PFOA among men in the general population?

Many epidemiological studies use a single blood sample per participant to assess exposure, but it is unclear how well a single sample represents longer term exposure. We performed a simulation study using summary statistics for repeated serum PFOA measurements from several previous studies in men to generate plausible serum concentrations over time, taking within-subject correlations into account. Simulated serum concentrations for controls were categorized into quintiles at each time point, and used to determine the extent of misclassification at each time point compared to the “true” long-term average exposure. We then generated case counts by quintile needed to produce an odds ratio (OR) of 1.5 for the highest vs. lowest quintile categorized based on long term exposure, and used the same misclassification rates observed in the controls to simulate misclassified exposure quintiles for cases. Comparing long term vs. single baseline exposure measures for repeated serum samples collected within about 5–13 years of each other revealed similar effect estimates, although there was a small bias to the null. Trend tests across quintiles were mostly significant using either baseline or long-term exposure. For the general population sample of men in Norway, with 5 repeated measurements over 28 years, serum PFOA was substantially lower prior to 1987, and using either of the two earliest samples as the exposure metric, compared to the long term average, produced larger bias to the null and non-significant trend tests; however using later time points as the exposure metric resulted in only a small bias. Using data based on studies of men, single baseline serum samples represented rather well the mean of repeated samples collectedup to 13 years apart, but were not always reliable surrogates for average exposure over 3 decades, during which time PFOA exposure levels in the general population have changed substantially.

Self-reported symptoms associated with the use of printer and photocopier machines: Results from the nano-Control, International Foundation survey.

To document adverse health effects among office, copy and print shop workers using the nano-Control International Organization Survey. Self-reported information on 16 health outcomes and three surrogate exposure variables were collected from 1998 individuals between 1999-2010. Logistic regression models, adjusted for age, gender, and smoking status, assessed the association between printer exposure and health symptoms. Among the participants, 61.9 % were office workers, 5.5% technicians and 23.3% held other professions. Technicians had a higher risk for cancer compared to office workers (OR = 2.5, p-value <0.01). Visible toner dust exposure was associated with chronic fatigue (OR = 9.6, <0.01), bronchial hyperresponsiveness (OR = 5.1, <0.01), cardiovascular diseases (OR = 3.6, <0.01), asthma, allergies, and other diseases (OR range 1.4 -3.2, <0.01). The increased chronic and acute health risks among these workers warrant further investigations of causal associations.

Distinguishing urban-rural difference in Chinese population exposure to ambient air pollutants

Using outdoor concentrations as surrogates of human exposure to ambient air pollutants introduces significant errors, as people spend the majority of their lives indoors. The infiltration factor and exposure factor are widely employed to modify outdoor-originated air pollution exposure. However, previous studies of the Chinese population lacked sufficient data on rural residents, limiting the representativeness and accuracy of the results. Here, we modeled the infiltration factor and exposure factor of five ambient air pollutants (NO2, SO2, O3, PM2.5 and PM10) in both rural and urban areas across 31 Chinese provinces and conducted field experiments in Beijing, Yunnan, Guizhou and Sichuan Provinces for 8 months to validate the modeling results. The infiltration factor and exposure factor vary between different air pollutants, with the exposure factor of PM2.5 reaching 70% for rural residents. Additionally, we found significant regional, seasonal, gender, and age differences between the urban and rural modification factors: infiltration and exposure factors in rural areas are generally greater than those in urban areas, especially in Northeast China; and the urban‒rural exposure disparity is most pronounced during winter, with a relative difference of up to 28% for SO2. The results are expected to be applied to modify population exposure to ambient air pollutants among Chinese urban and rural residents, promote accurate estimations of population health risks and further contribute to the implementation of targeted interventions.

The association between 2D:4D digit ratio and sex-typed play in children with and without siblings

The 2D:4D digit ratio is commonly used as a surrogate possibly reflecting prenatal testosterone levels. Indirect evidence comes from studies investigating the association between 2D:4D and human characteristics that likely relate to prenatal testosterone. In children, sex-typed play reveals large sex differences early in development and an influence of prenatal testosterone is likely. Findings on the association between 2D:4D and children’s sex-typed play are heterogeneous and other influences on the development of sex-typed play have been suggested, most of all social influences like siblings, their sex and birth order. The current study examined the association between right and left 2D:4D, a proposed surrogate for prenatal testosterone exposure, which was assessed in right and left hands of N = 505 6-month-old children, and sex-typed play behavior, which was evaluated 3.5 years later using the Pre-School Activities Inventory (PSAI), and the influence of siblings. To capture differential effects of siblings’ sex and birth order, dummy-coded variables were used reflecting having no siblings as well as older or younger sisters or brothers. Multiple regression models were used to investigate the association between PSAI scores and sex, right and left 2D:4D, being a singleton as well as having an older or younger sister or brother. It was shown that sex and having an older brother were significant predictors for sex-typed play. Effects were further disentangled by conducting separate regression analyses in boys and girls. In boys, a significant association between PSAI scores and having an older brother was revealed, in girls, no significant associations were found. Results are discussed highlighting the non-significant association between 2D:4D and children’s sex-typed play, which weakens the applicability of 2D:4D as a surrogate reflecting influences of prenatal T. Further, the importance of social factors like siblings on children’s sex-typed play is discussed.

Personal exposure monitoring of fine and coarse particulate matter using exposure assessment models for elderly residents in Hong Kong

This study investigated the determinants of personal exposures (PE) to coarse (PM2.5-10) and fine particulate matter (PM2.5) for elderly communities in Hong Kong. The mean PE PM2.5 and PM2.5-10 were 23.6 ± 10.8 and 13.5 ± 22.1 μg/m3, respectively during the sampling period. Approximately 76% of study subjects presented statistically significant differences between PE and ambient origin for PM2.5 compared to approximately 56% for PM2.5-10, possibly due to the coarse-size particles being more influenced by similar sources (road dust and construction dust emissions) compared to the PM2.5 particles. Individual PE to ambient (P/A) ratios for PM2.5 all exceeded unity (≥1), suggesting the dominant influences of non-ambient particles contributed towards total PE values. There were about 80% individual P/A ratios (≤1) for PM2.5-10, implying possible effective infiltration prevention of larger size particulate matter particles leading to dominant influences from the outdoor sources. The higher concentration of NO3− and SO42− in PM2.5-10 compared to PM2.5 suggests possible heterogeneous reactions of alkaline minerals leading to the formation of NO3− and SO42− in PM2.5-10 particles. The PE and ambient OC/EC ratios in PM2.5 (8.8 ± 3.3 and 10.4 ± 22.4, respectively) and in PM2.5-10 (6.0 ± 1.9 and 3.0 ± 1.1, respectively) suggest possible secondary formed OC from surrounding rural areas. Heterogeneous distributions (COD >0.2) between the PE and ambient concentrations were found for both the PM2.5 and PM2.5-10 samples. The calibration coefficient as the association between personal and surrogate exposure measure of PE to PM2.5 (0.84) was higher than PM2.5-10 (0.52). The findings further confirm that local sources were the dominant contributor to the coarse particles and these coefficients can potentially be used to estimate different PE to PM2.5 and PM2.5-10 conditions. A comprehensive understanding of the PE to determinants in coarse particles is essential to further reduce potential exposure misclassification.

Inverse association between plasma chlordecone concentrations and progression of alcoholic liver fibrosis: the role of liver metabolism

Background and AimsChlordecone is a persistent organochlorinated insecticide, extensively used in the French West Indies and has been contaminating the population for more than thirty years. Its potentiation effect on hepatotoxic agents has been demonstrated in animal models. We investigated the relationship between environmental exposure to chlordecone and the progression of liver fibrosis.MethodsThis study included 182 consecutive patients with chronic alcoholic hepatitis whose liver fibrosis was assessed using non-invasive methods. Measured plasma chlordecone concentrations at inclusion were used as surrogate of long-term exposure under steady-state conditions. As the pharmacokinetic processing of chlordecone is largely determined by the liver, we used a human physiologically based pharmacokinetic model to predict plausible changes in the steady-state blood chlordecone concentrations induced by liver fibrosis.ResultsWith a median follow-up of 27.1 years after the onset of alcohol consumption, we found a significant decrease in the risk of advanced liver fibrosis with increasing plasma chlordecone concentration (adjusted hazard ratio = 0.56; 95% confidence interval: 0.34–0.95 for the highest vs. lowest tertile, p = 0.04). Changes induced by liver fibrosis influenced the pharmacokinetic processing of chlordecone, resulting in substantial modifications in its steady-state blood concentrations.ConclusionAccording to this human model of coexposure to alcohol, reverse causality is the most plausible explanation of this inverse association between plasma chlordecone concentrations and progression of liver fibrosis. This study underlines the importance of considering the pharmacokinetic of environmental contaminants in epidemiological studies when biomarkers of exposure are used to investigate their own impact on the liver.Trial registrationClinicalTrials.gov Identifier: NCT03373396.

Sleep disorders and cancer incidence: examining duration and severity of diagnosis among veterans.

Sleep disruption affects biological processes that facilitate carcinogenesis. This retrospective cohort study used de-identified data from the Veterans Administration (VA) electronic medical record system to test the hypothesis that patients with diagnosed sleep disorders had an increased risk of prostate, breast, colorectal, or other cancers (1999-2010, N=663,869). This study builds upon existing evidence by examining whether patients with more severe or longer-duration diagnoses were at a greater risk of these cancers relative to those with a less severe or shorter duration sleep disorder. Incident cancer cases were identified in the VA Tumor Registry and sleep disorders were defined by International Classification of Sleep Disorder codes. Analyses were performed using extended Cox regression with sleep disorder diagnosis as a time-varying covariate. Sleep disorders were present among 56,055 eligible patients (8% of the study population); sleep apnea (46%) and insomnia (40%) were the most common diagnoses. There were 18,181 cancer diagnoses (41% prostate, 12% colorectal, 1% female breast, 46% other). The hazard ratio (HR) for a cancer diagnosis was 1.45 (95% confidence interval [CI]: 1.37, 1.54) among those with any sleep disorder, after adjustment for age, sex, state of residence, and marital status. Risks increased with increasing sleep disorder duration (short [<1-2 years] HR: 1.04 [CI: 1.03-1.06], medium [>2-5 years] 1.23 [1.16-1.32]; long [>5-12 years] 1.52 [1.34-1.73]). Risks also increased with increasing sleep disorder severity using cumulative sleep disorder treatments as a surrogate exposure; African Americans with more severe disorders had greater risks relative to those with fewer treatments and other race groups. Results among patients with only sleep apnea, insomnia, or another sleep disorder were similar to those for all sleep disorders combined. The findings are consistent with other studies indicating that sleep disruption is a cancer risk factor. Optimal sleep and appropriate sleep disorder management are modifiable risk factors that may facilitate cancer prevention.

Association between High Antimetabolite Dose Intensity during Maintenance, Toxicities and Relapse Risk in Children with Acute Lymphoblastic Leukemia (ALL): COG-AALL03N1 Report

Introduction: Current COG protocols for childhood ALL recommend increasing 6-mercaptopurine (6MP) and methotrexate (MTX) dose intensity (DI=prescribed therapy dose/ planned protocol dose) to &amp;gt;100% during maintenance for patients exhibiting inadequate myelosuppression (surrogate for systemic exposure to 6MP/MTX). Whether increasing DI &amp;gt;100% (high DI) to achieve myelosuppression is associated with increased toxicity is not clear. Additionally, whether high DI influences relapse risk, and the direction of that association, remains unknown. Nonadherence to 6MP results in inadequate myelosuppression and prompts clinicians to increase the prescribed dose. Nonadherence to 6MP is also associated with relapse (Bhatia, JAMA Onc 2015). Prior literature examining the association between high DI and relapse risk did not consider adherence to chemotherapy. Here, we examined whether high 6MP/MTX DI affects toxicity or relapse, taking 6MP adherence into consideration. Methods: We used data collected by COG-AALL03N1 (primary aim: 6MP adherence and risk of relapse) to examine the association between high DI and (i) hematologic toxicity, and (ii) relapse risk. Inclusion criteria: (i) age &amp;lt;21y at ALL diagnosis, (ii) receiving maintenance therapy in first remission and &amp;gt;6mo since starting maintenance, (iii) wild-type thiopurine methyltransferase ( TPMT) or nucleoside diphosphate-linked motif 15 (NUDT15) and (iv) objectively measured 6MP adherence for 6mo per patient (using MEMS-TrackCaps). 6MPDI and MTXDI were calculated monthly for 6mo. Updates on vital status, relapse or second neoplasm were collected every 6mo-1y from participating sites for up to 10y. Exposure: ‘high DI’ phenotype: (i) 6MPDI or MTXDI ≥110% at any time during the first 4 study months, or (ii) 6MPDI or MTXDI 100% to 110% at study enrollment and ≥25% increase over the first 4 study months. All other patients were categorized as having ‘normal DI’. Outcomes: (i) hematologic toxicity (absolute neutrophil count &amp;lt;500 cells/µL, platelet count &amp;lt;50,000 cells/mm 3, or treatment interruption due to low ANC/platelets) during the subsequent 2 study months (months 5 and 6); and (ii) ALL relapse any time after month 4. We used logistic regression to examine the association between high DI and hematologic toxicity, adjusting for age at study entry, sex, race/ethnicity. The association between DI and relapse was estimated using proportional sub-distribution hazard regression models, adjusting for age at study entry, blast cytogenetics, time from start of maintenance, and treatment interruptions. Analyses were stratified by 6MP adherence (adherers: median adherence ≥85%; non-adherers: median adherence &amp;lt;85%). Adherence was included in both models to account for residual confounding. Results: Characteristics of the 410 eligible participants are summarized in the Table; the cohort was followed for a median 7.9y (range, 0.2-13). There were no significant differences between patients with normal (71.5%) vs high (28.5%) DI. Patients with high DI had lower median 6MP adherence (94.6% vs 97.0%, P=0.02). Hematologic DLT: As shown in the Figure, the proportion of patients with hematologic toxicities was significantly higher among adherers with high DI compared with adherers with normal DI (38.1% vs 18.5%, P=0.0003). In contrast, the proportion of patients with hematologic toxicities was not significantly different by DI status among non-adherers (18.5% vs 10.5%, P=0.4). Multivariable analysis revealed that high DI was associated with 2.9-fold greater odds of hematologic toxicity among adherers (95%CI=1.6-5.1, P&amp;lt;0.001) and a non-significant 2.1-fold greater odds of hematologic toxicity among non-adherers (95%CI=0.4-10.1, P=0.4). Relapse risk: The adjusted hazard of relapse among adherent patients exposed to high DI was 2.2-fold greater (95%CI=1.0-5.1, P=0.06) than adherent patients exposed to normal DI after adjusting for covariates. In contrast, the hazard of relapse among non-adherent patients exposed to high DI (vs. normal DI) was not elevated (HR=0.9, 95%CI=0.2-3.8, P=0.8). Conclusions: High antimetabolite dose intensity in children with ALL who adhere to oral 6MP during maintenance therapy is associated with higher odds of hematologic toxicities as well as increased hazard of relapse. These findings inform clinicians about the issues related to dose escalation beyond protocol doses, especially among adherent patients.

Adjusting for Berkson error in exposure in ordinary and conditional logistic regression and in Poisson regression

BackgroundINTEROCC is a seven-country cohort study of occupational exposures and brain cancer risk, including occupational exposure to electromagnetic fields (EMF). In the absence of data on individual exposures, a Job Exposure Matrix (JEM) may be used to construct likely exposure scenarios in occupational settings. This tool was constructed using statistical summaries of exposure to EMF for various occupational categories for a comparable group of workers.MethodsIn this study, we use the Canadian data from INTEROCC to determine the best EMF exposure surrogate/estimate from three appropriately chosen surrogates from the JEM, along with a fourth surrogate based on Berkson error adjustments obtained via numerical approximation of the likelihood function. In this article, we examine the case in which exposures are gamma-distributed for each occupation in the JEM, as an alternative to the log-normal exposure distribution considered in a previous study conducted by our research team. We also study using those surrogates and the Berkson error adjustment in Poisson regression and conditional logistic regression.ResultsSimulations show that the introduced methods of Berkson error adjustment for non-stratified analyses provide accurate estimates of the risk of developing tumors in case of gamma exposure model. Alternatively, and under some technical assumptions, the arithmetic mean is the best surrogate when a gamma-distribution is used as an exposure model. Simulations also show that none of the present methods could provide an accurate estimate of the risk in case of stratified analyses.ConclusionWhile our previous study found the geometric mean to be the best exposure surrogate, the present study suggests that the best surrogate is dependent on the exposure model; the arithmetic means in case of gamma-exposure model and the geometric means in case of log-normal exposure model. However, we could present a better method of Berkson error adjustment for each of the two exposure models. Our results provide useful guidance on the application of JEMs for occupational exposure assessments, with adjustment for Berkson error.

Estimation of infiltration efficiency of ambient PM2.5 in urban residences of Beijing during winter

Fine particulate matter pollution has become a major public health concern in the urban areas of China. Ambient PM2.5 concentrations measured at fixed sites are commonly used as an exposure surrogate, although exposure to ambient PM2.5 primarily occurs in indoor environments. In this study, valid indoor and outdoor mass concentrations of PM2.5 during winter, were concurrently measured in 26 urban residences in Beijing. The infiltration factor (Finf), defined as the fraction of ambient PM2.5 which penetrates indoors and remains suspended, was estimated using a recursive model. The environmental conditions that significantly influenced Finf were screened using a general linear model and multiple regression analysis. Finf during winter was 0.52 ± 0.25 with large home-by-home variability. The results suggested that: (1) infiltration from outdoor to indoor environments remarkably reduced the concentrations of ambient PM2.5; and (2) using ambient PM2.5, as an exposure surrogate, can result in exposure misclassification. Improved ventilation was found to increase Finf, whereas an increase in indoor RH from 19.20 to 51.30% resulted in a reduction in Finf. The residences proximate to arterial roads were found to be prone for the infiltration of ambient PM2.5. There were remarkable seasonal differences in the infiltration behavior of ambient PM2.5.

The challenges of defining hormesis in epidemiological studies: The case of radiation hormesis

In the current radiation protection system, preventive measures and occupational exposure limits for controlling occupational exposure to ionizing radiation are based on the linear no-threshold extrapolation model. However, currently an increasing body of evidence indicates that this paradigm predicts very poorly biological responses in the low-dose exposure region. In addition, several in vitro and in vivo studies demonstrated the presence of hormetic dose response curves correlated to ionizing radiation low exposure. In this regard, it is noteworthy that also the findings of different epidemiological studies, conducted in different categories of occupationally exposed workers (e.g., healthcare, nuclear industrial and aircrew workers), observed lower rates of mortality and/or morbidity from cancer and/or other diseases in exposed workers than in unexposed ones or in the general population, then suggesting the possible occurrence of hormesis. Nevertheless, these results should be considered with caution since the identification of hormetic response in epidemiological studies is rather challenging because of a number of major limitations. In this regard, some of the most remarkable shortcomings found in epidemiological studies performed in workers exposed to ionizing radiation are represented by lack or inadequate definition of exposure doses, use of surrogates of exposure, narrow dose ranges, lack of proper control groups and poor evaluation of confounding factors. Therefore, considering the valuable role and contribution that epidemiological studies might provide to the complex risk assessment and management process, there is a clear and urgent need to overcome the aforementioned limits in order to achieve an adequate, useful and more real-life risk assessment that should also include the key concept of hormesis. Thus, in the present conceptual article we also discuss and provide possible approaches to improve the capacity of epidemiological studies to identify/define the hormetic response and consequently improve the complex process of risk assessment of ionizing radiation at low exposure doses.

An LC-ESI-MS/MS method for determination of ondansetron in low-volume plasma and cerebrospinal fluid: Method development, validation, and clinical application

Ondansetron is used in clinical settings as an antiemetic drug. Although the animal studies showed its potential effectiveness also in treating neuropathic pain, the results from humans are inconclusive. The lack of efficacy of ondansetron in a subset of patients might be due to the overexpression of P-glycoprotein, which could result in low concentrations of ondansetron in the central nervous system (CNS). A surrogate of the CNS exposure might be drug concentration in the cerebrospinal fluid (CSF), especially in humans, as assessing the drug disposition directly in the patient’s brain would be challenging. The study aimed to develop a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine concentrations of ondansetron in human K3EDTA plasma and CSF. Ondansetron was extracted from biological matrices by liquid-liquid extraction. The quantification was performed on a Sciex QTRAP 6500+ mass spectrometer with labeled ondansetron as an internal standard. The calibration range was 0.25–350 ng/mL in plasma and 0.025–100 ng/mL in CSF; for both matrices, 25 µL of samples was required for the assays. The method was validated according to the FDA and EMA guidelines and showed acceptable results. A pilot study confirmed its suitability for clinical samples: after 4–16 mg of intravenous ondansetron, the determined concentrations in plasma were 1.22–235.90 ng/mL, while in CSF - 0.018–11.93 ng/mL. In conclusion, the developed method fulfilled all validation requirements and can be applied to pharmacokinetic studies assessing the CNS ondansetron exposure in humans. The method’s advantages, such as a low volume of matrix and a wide calibration range, support its use in a study in which rich sampling and various drug doses are expected.

Modeling and Simulation as a Tool to Assess Voriconazole Exposure in the Central Nervous System.

Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: Km = 4.76 mg/L, Vmax = 1.06 mg/h, Q1 = 2.69 L, Qin = 0.81 h-1 and Qout = 0.63 h-1. Infection was a covariate in the Michaelis-Menten constant (Km) and intercompartmental clearance from the brain tissue compartment to central compartment (Qout). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations.

Correlation of mean apparent diffusion coefficient (ADC) and maximal standard uptake value (SUVmax) evaluated by diffusion-weighted MRI and 18F-FDG-PET/CT in children with Hodgkin lymphoma: a feasibility study.

The objective was to analyse if magnetic resonance imaging (MRI) can act as a non-radiation exposure surrogate for (18)F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in children with histologically confirmed Hodgkin lymphoma (HL) before treatment. This was done by analysing a potential correlation between apparent diffusion coefficient (ADC) in MRI and the maximum standardized uptake value (SUVmax) in FDG-PET/CT. Seventeen patients (six female, eleven male, median age: 16 years, range: 12-20 years) with histologically confirmed HL were retrospectively analysed. The patients underwent both MRI and (18)F-FDG PET/CT before the start of treatment. (18)F-FDG PET/CT data and correlating ADC maps in MRI were collected. For each HL-lesion two readers independently evaluated the SUVmax and correlating meanADC. The seventeen patients had a total of 72 evaluable lesions of HL and there was no significant difference in the number of lesions between male and female patients (median male: 15, range: 12-19 years, median female: 17 range: 12-18 years, p = 0.021). The mean duration between MRI and PET/CT was 5.9 ± 5.3 days. The inter-reader agreement as assessed by the intraclass correlation coefficient (ICC) was excellent (ICC = 0.98, 95% CI: 0.97-0.99). The correlated SUVmax and meanADC of all 17 patients (ROIs n = 72) showed a strong negative correlation of -0.75 (95% CI: -0.84, - -0.63, p = 0.001). Analysis revealed a difference in the correlations of the examination fields. The correlated SUVmax and meanADC showed a strong correlation at neck and thoracal examinations (neck: -0.83, 95% CI: -0.93, - -0.63, p < 0.0001, thoracal: -0.82, 95% CI: -0.91, - -0.64, p < 0.0001) and a fair correlation at abdominal examinations of -0.62 (95% CI: -0.83, - -0.28, p = 0.001). SUVmax and meanADC showed a strong negative correlation in paediatric HL lesions. The assessment seemed robust according to inter-reader agreements. Our results suggest that ADC maps and meanADC have the potential to replace PET/CT in the analysis of disease activity in paediatric Hodgkin lymphoma patients. This may help reduce the number of PET/CT examinations and decrease radiation exposure to children.

PD34-09 THE ASSOCIATION BETWEEN ORGANOPHOSPHATE INSECTICIDES AND KIDNEY STONE FORMATION AMONG U.S. ADULTS

You have accessJournal of UrologyCME1 Apr 2023PD34-09 THE ASSOCIATION BETWEEN ORGANOPHOSPHATE INSECTICIDES AND KIDNEY STONE FORMATION AMONG U.S. ADULTS Frank Glover, Mohammad Hajiha, Michael Eisenberg, Federico Belladelli, Francesco Del Giudice, Nicolas Seranio, Wade Muncey, and Kenneth Ogan Frank GloverFrank Glover More articles by this author , Mohammad HajihaMohammad Hajiha More articles by this author , Michael EisenbergMichael Eisenberg More articles by this author , Federico BelladelliFederico Belladelli More articles by this author , Francesco Del GiudiceFrancesco Del Giudice More articles by this author , Nicolas SeranioNicolas Seranio More articles by this author , Wade MunceyWade Muncey More articles by this author , and Kenneth OganKenneth Ogan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003327.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Kidney stones pose a significant disease burden within the U.S., where an estimated 10% of adults are affected. While several risk factors have been identified in the etiology of kidney stones (e.g., hydration status, diet, and genetic conditions) the pathogenesis remains to be fully elucidated. Recently, the contribution of environmental exposures in the pathogenesis of adverse urological outcomes has gained attention though data is limited. Organophosphate (OP) insecticides are widespread toxicants, and their use has been associated with endocrine disruption, metabolic dysregulation, and increased risk of chronic diseases. Currently, the association between kidney stone formation and OP exposure is unknown. The purpose of this study was to investigate the relationship between OP exposure and kidney stones. METHODS: Data for nationally representative U.S. cohort of 2373 individuals was leveraged from the National Health and Nutrition Examination (NHANES) Survey, annually conducted, population-based cross-sectional study. Trained individuals collected biological specimens via blood and urine draws, and sociodemographic data via in-person questionnaires. Urinary measurements of dialkyl phosphates (DAPs) were used as surrogates for OP exposure. Kidney stone history was evaluated based on questionnaire data, where individuals with kidney stones responded “yes” to either ever having kidney stones, or passed a kidney stone within the last year. Chi-square, ANOVA and multivariable, weighted logistic regression were used to analyze the relationship between DAP exposure, sociodemographic variables, and history of kidney stones. RESULTS: Stratification of total urinary DAPs by quartiles revealed a significant increased odds of kidneys stones in the fourth quartile compared to the first quartile (Q2 OR=1.65 95%CI [0.72,3.77], Q3 OR=2.72 95%CI [0.92,7.99], Q4 OR=3.08 95%CI [1.05,9.01]. CONCLUSIONS: Our study represents the first evaluation of OP exposure on risk of kidney stone formation, and these preliminary results suggest a potential role for OP exposure in the pathogenesis of kidney stone formation. Future studies are warranted to validate these findings, and to investigate potential mechanisms underlying these associations. Source of Funding: No funding © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e923 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Frank Glover More articles by this author Mohammad Hajiha More articles by this author Michael Eisenberg More articles by this author Federico Belladelli More articles by this author Francesco Del Giudice More articles by this author Nicolas Seranio More articles by this author Wade Muncey More articles by this author Kenneth Ogan More articles by this author Expand All Advertisement PDF downloadLoading ...

Degree of Actinic Elastosis Is a Surrogate of Exposure to Chronic Ultraviolet Radiation and Correlates More Strongly with Cutaneous Squamous Cell Carcinoma than Basal Cell Carcinoma.

(1) Background: Keratinocyte cancer (KC) is associated with exposure to ultraviolet (UV) radiation. However, data are controversial as to whether chronic UV exposure or high intermittent UV exposure are key drivers of carcinogenesis in cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Prolonged sun exposure of the skin causes photo-aging, which is associated with actinic elastosis, a condition characterized by the degeneration of elastin in the upper dermis, which is assessable via conventional histology. In this study, we aimed to compare the degree of actinic elastosis in different types of KC with regard to various patient characteristics. (2) Methods: We defined a semiquantitative score for the degree of actinic elastosis ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration). The extent was measured histometrically by two independent dermatohistopathologists in the immediate vicinity of 353 KC. The scores were merged and matched with tumor types (cSCC and BCC with subtypes), and clinical variables such as body site, sex and age. (3) Results: As expected, the degree of actinic elastosis correlated with age. However, it was significantly higher in cSCC compared to BCC irrespective of age, sex, body site and tumor subtypes. (4): Conclusions: Lifetime sun exposure may be estimated via routine histology using this scoring technique for actinic elastosis as a surrogate marker. cSCCs are more strongly associated with chronic UV exposure than BCCs, even in sun-exposed localizations such as the face.

Co-exposure to toxic metals and phthalates in pregnant women and their children’s mental health problems aged four years — Taiwan Maternal and Infant Cohort Study (TMICS)

BackgroundChildhood and adolescent mental health problems may increase the global burden of disease. Neurotoxic metals are associated with inflammation and cytotoxicity in the brain. In addition, prenatal phthalate ester (PAE) exposure is associated with cognitive function deficits. However, the effect of co-exposure to toxic metals, PAEs, and their association with child behavior is less well studied. Hence, we aimed to investigate prenatal co-exposure to the metals and PAEs and the consequent behavioral outcomes in early childhood. MethodsWe followed pregnant women and their newborns from the Taiwan Maternal and Infant Cohort Study between 2015 and 2017, with a focus on women from the central, southern, and eastern areas of Taiwan. We quantified maternal urinary concentrations of metals and metabolites of PAEs as surrogates of prenatal exposure. We recorded the Child Behavior Checklist scores according to caregiver reports at 4 years of age, and identified Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)-oriented problems. ResultsUltimately, 408 children were included in the statistical analysis. Maternal urinary copper levels were significantly associated with depressive problems (odds ratio [OR] = 2.13) in children. Maternal urinary concentrations of mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) were also significantly associated with depressive symptoms (odds ratio [OR] = 1.51 and 1.53, respectively). Further analysis considering prenatal co-exposure to metals and PAEs showed that co-exposure to these materials was significantly associated with autism spectrum problems (OR = 3.11). ConclusionsWe observed that prenatal single exposure or co-exposure to metals and PAEs may play a role in some DSM-5-oriented problems in children at 4 years of age. Reduction of exposure to toxic metals and PAEs in pregnancy is suggested to prevent increased mental health problems in children.

Adjusting for misclassification of an exposure in an individual participant data meta-analysis.

A common problem in the analysis of multiple data sources, including individual participant data meta-analysis (IPD-MA), is the misclassification of binary variables. Misclassification may lead to biased estimators of model parameters, even when the misclassification is entirely random. We aimed to develop statistical methods that facilitate unbiased estimation of adjusted and unadjusted exposure-outcome associations and between-study heterogeneity in IPD-MA, where the extent and nature of exposure misclassification may vary across studies. We present Bayesian methods that allow misclassification of binary exposure variables to depend on study- and participant-level characteristics. In an example of the differential diagnosis of dengue using two variables, where the gold standard measurement for the exposure variable was unavailable for some studies which only measured a surrogate prone to misclassification, our methods yielded more accurate estimates than analyses naive with regard to misclassification or based on gold standard measurements alone. In a simulation study, the evaluated misclassification model yielded valid estimates of the exposure-outcome association, and was more accurate than analyses restricted to gold standard measurements. Our proposed framework can appropriately account for the presence of binary exposure misclassification in IPD-MA. It requires that some studies supply IPD for the surrogate and gold standard exposure, and allows misclassification to follow a random effects distribution across studies conditional on observed covariates (and outcome). The proposed methods are most beneficial when few large studies that measured the gold standard are available, and when misclassification is frequent.

A 12-Year Audit of Neurological Outcomes Associated with Core Body Temperature >37.5°C in Children with Severe Traumatic Brain Injury.

Hyperthermia exposure is associated with poor neurological outcomes in patients with severe traumatic brain injury (TBI). Our aim was to describe fever in children with severe TBI admitted to a pediatric intensive care unit (PICU) for at least 72 hours and to evaluate associations between fever using a novel approach to describe thermal exposure and neurobehavioral outcomes. The cohort included children from birth to 17 years of age admitted to the PICU between 2000 and 2012 for at least 72 hours who had severe TBI with intracranial pressure monitoring. Patients with non-accidental TBI or pre-existing developmental delays were excluded. Hyperthermia was defined as a core temperature >37.5°C. Hourly temperature measurements were used to calculate the area under the curve (AUC) using the linear trapezoidal rule. Each participant was followed up at the Brain Injury Clinic 6 and 18 months postinjury. Neurobehavioral outcome scores were analyzed against AUC using standard statistical methods. Ninety-eight patients admitted with severe TBI met the study inclusion criteria. Hyperthermia/fever was common (89.7%), and patients remained hyperthermic for a median of 9.4 hours. However, no statistically significant association was found between AUC and abnormal neurological outcomes. The follow-up rates were good at 6 (86.7%) and 18 months (83.7%). The neurological deficit improved with time, with "favorable outcomes" increasing from 72% to 94% at the respective follow-up months. Our study used a novel method to describe patients' fever, providing a different indicator of thermal exposure than that previously reported. In addition, the AUC was well correlated with the maximum temperature recorded and the proportion of time >37.5°C, indicating that it is a good surrogate for thermal exposure. Interestingly, the neurological disabilities of the patients improved over time.

Supraventricular cardiac conduction system exposure in breast cancer patients treated with radiotherapy and association with heart and cardiac chambers doses

PurposeTo assess sinoatrial node (SAN) and atrioventricular node (AVN) doses for breast cancer (BC) patients treated with 3D-CRT and evaluate whether “large” cardiac structures (whole heart and four cardiac chambers) would be relevant surrogates. Material and methodsThis single center study was based on 116 BCE patients (56 left-sided, 60 right-sided) treated with 3D-CRT without respiratory gating strategies and few IMN irradiations from 2009 to 2013. The heart, the left and right ventricles (LV, RV), the left and right atria (LA, RA) were contoured using multi-atlases for auto-segmentation. The SAN and the AVN were manually delineated using a specific atlas. Based on regression analysis, the coefficients of determination (R2) were estimated to evaluate whether “large” cardiac structures were relevant surrogates (R2 > 0.70) of SAN and AVN doses. ResultsFor left-sided BC, mean doses were: 3.60 ± 2.28 Gy for heart, 0.47 ± 0.24 Gy for SAN and 0.74 ± 0.29 Gy for AVN. For right-sided BC, mean heart dose was 0.60 ± 0.25 Gy, mean SAN dose was 1.57 ± 0.63 Gy (>85 % of patients with SAN doses > 1 Gy) and mean AVN dose was 0.51 ± 0.14 Gy. Among all “large” cardiac structures, RA appeared as the best surrogate for SAN doses (R2 > 0.80). Regarding AVN doses, the RA may also be an interesting surrogate for left-sided BC (R2 = 0.78), but none of “large” cardiac structures appeared as relevant surrogates among right-sided BC (all R2 < 0.70), except the LA for patients with IMN (R2 = 0.83). ConclusionsIn BC patients treated 10 years ago with 3D-CRT, SAN and AVN exposure was moderate but could exceed 1 Gy to the SAN in many right-sided patients with no IMN-inclusion. The RA appeared as an interesting surrogate for SAN exposure. Specific conduction nodes delineation remains necessary by using modern radiotherapy techniques.